1. Field of the Invention
This invention relates to methods and compositions for regulating the insulin signaling pathway and for the treatment of metabolic syndrome, including insulin resistance and diabetes mellitus type II.
2. Description of Related Art
G protein-coupled receptor kinases (GRKs) play a central role in desensitizing G protein-coupled receptors (GPCRs). G protein coupled receptor kinases (GRKs) are enzymes which phosphorylate agonist-activated 7TMRs, leading to 7TMR internalization and inhibition of further G protein activation. GRKs also have other functions to regulate 7TMR signaling. Thus, GRKs directly bind to trimeric G protein 1-subunits, and inhibit G protein function. GRKs also phosphorylate specific C-terminal serine residues of agonist-activated GPCRs, leading to increased binding of β-arrestin. GRK-induced phosphorylation of the GPCR, with subsequent β-arrestin association, uncouples the receptors from further G protein association, and also promotes internalization of the GPCR. It has also been shown that GRKs have additional functions to regulate GPCR signaling. Thus, it is believed that GRKs can contain RGS domains which mediate binding to Gα subunits, inhibiting G protein function.
Endothelin-1 (ET-1) is a vascular polypeptide primarily secreted by endothelial cells. Elevated plasma ET-1 levels have been reported in patients with insulin resistance, such as type 2 diabetes, obesity, and hypertension. ET-1 initiates its actions by binding to the 7 transmembrane receptor (7TMR), endothelin type A receptor.
The insulin receptor, on the other hand, is a receptor tyrosine kinase (RTK), which activates its signaling cascade by phosphorylating various intracellular substrates, including IRS-1, IRS-2, Shc, and G protein-q/11 α-subunit (Gαq/11). Insulin also promotes glucose transport by stimulating translocation of GLUT4 proteins to the cell surface. Activated insulin receptor is believed to be able to phosphorylate the heterotrimeric protein component Gαq/11, leading to activation of cdc42, and PI3-kinase with downstream glucose transport stimulation.
Although much is known about these biochemical components of metabolic syndrome, what has not been determined is a mechanism for producing insulin sensitivity or attenuation of insulin resistance to provide a target for drug studies for the treatment of metabolic syndrome. Therefore, what are needed are methods for designing such drugs and treatments for metabolic syndrome and methods for screening for insulin resistance levels.